Cigarette smoking and colorectal cancer risk by molecularly defined subtypes

David Limsui, Robert A. Vierkant, Lori S. Tillmans, Alice H. Wang, Daniel J. Weisenberger, Peter W. Laird, Charles F. Lynch, Kristin E. Anderson, Amy J. French, Robert W. Haile, Lisa J. Harnack, John D. Potter, Susan L Slager, Thomas Christopher Smyrk, Stephen N Thibodeau, James R Cerhan, Paul John Limburg

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Abstract

Background Cigarette smoking is an established risk factor for colorectal cancer. Because colorectal carcinogenesis is a heterogeneous process, we investigated whether cigarette smoking is differentially associated with molecularly defined subtypes of colorectal cancer.Methods We evaluated associations between smoking and incident colorectal cancer, overall and by microsatellite instability (MSI) phenotype (MSI-high vs MSI-low or microsatellite stable), CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation status (BRAF mutation positive or BRAF mutation negative), among 37399 participants in a population-based cohort study (the Iowa Women's Health Study). Cigarette smoking (and other exposures) was assessed by self-report at baseline in 1986, including smoking status (never and ever [former or current]), age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period. Vital status and state of residence were determined by mailed follow-up questionnaires in 1987, 1989, 1992, and 1997 and by linkage to Iowa death certificate records. Nonrespondents were checked via the National Death Index to identify descendants. Participants with newly diagnosed (ie, incident) colorectal cancer were identified through annual linkage with the Iowa Cancer Registry. Archived paraffin-embedded tumor tissue specimens were obtained for 555 patients with colorectal cancer who were diagnosed from January 1, 1986, through December 31, 2002, and MSI status, CIMP status, and BRAF status were determined. Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results Ever-smokers were at moderately increased risk for incident colorectal cancer (RR = 1.19, 95% CI = 1.05 to 1.35) compared with never-smokers. Higher risk estimates were observed for current smokers with MSI-high tumors (RR = 1.99, 95% CI = 1.26 to 3.14), CIMP-positive tumors (RR = 1.88, 95% CI = 1.22 to 2.90), and BRAF mutation-positive tumors (RR = 1.92, 95% CI = 1.22 to 3.02). Other smoking-related variables (ie, age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period) were also associated with MSI-high, CIMP-positive, and BRAF mutation-positive tumor subtypes. Conversely, cigarette smoking status (ever vs never) was not associated with the MSI-low or microsatellite stable (RR = 1.00, 95% CI = 0.79 to 1.25), CIMP-negative (RR = 1.02, 95% CI = 0.81 to 1.30), or BRAF mutation-negative subtypes (RR = 1.00, 95% CI = 0.65 to 1.27). Conclusions In this prospective study of older women, cigarette smoking was associated with the MSI-high, CIMP-positive, and BRAF mutation-positive colorectal cancer subtypes, which indicates that epigenetic modification may be functionally involved in smoking-related colorectal carcinogenesis.

Original languageEnglish (US)
Pages (from-to)1012-1022
Number of pages11
JournalJournal of the National Cancer Institute
Volume102
Issue number14
DOIs
StatePublished - Jul 2010

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Microsatellite Instability
Colorectal Neoplasms
Smoking
Confidence Intervals
Mutation
Neoplasms
Death Certificates
Tobacco Products
Microsatellite Repeats
Carcinogenesis
Phenotype
CpG Islands
Women's Health
Proportional Hazards Models
Epigenomics
Paraffin
Self Report
Registries
Cohort Studies
Prospective Studies

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Limsui, D., Vierkant, R. A., Tillmans, L. S., Wang, A. H., Weisenberger, D. J., Laird, P. W., ... Limburg, P. J. (2010). Cigarette smoking and colorectal cancer risk by molecularly defined subtypes. Journal of the National Cancer Institute, 102(14), 1012-1022. https://doi.org/10.1093/jnci/djq201

Cigarette smoking and colorectal cancer risk by molecularly defined subtypes. / Limsui, David; Vierkant, Robert A.; Tillmans, Lori S.; Wang, Alice H.; Weisenberger, Daniel J.; Laird, Peter W.; Lynch, Charles F.; Anderson, Kristin E.; French, Amy J.; Haile, Robert W.; Harnack, Lisa J.; Potter, John D.; Slager, Susan L; Smyrk, Thomas Christopher; Thibodeau, Stephen N; Cerhan, James R; Limburg, Paul John.

In: Journal of the National Cancer Institute, Vol. 102, No. 14, 07.2010, p. 1012-1022.

Research output: Contribution to journalArticle

Limsui, D, Vierkant, RA, Tillmans, LS, Wang, AH, Weisenberger, DJ, Laird, PW, Lynch, CF, Anderson, KE, French, AJ, Haile, RW, Harnack, LJ, Potter, JD, Slager, SL, Smyrk, TC, Thibodeau, SN, Cerhan, JR & Limburg, PJ 2010, 'Cigarette smoking and colorectal cancer risk by molecularly defined subtypes', Journal of the National Cancer Institute, vol. 102, no. 14, pp. 1012-1022. https://doi.org/10.1093/jnci/djq201
Limsui D, Vierkant RA, Tillmans LS, Wang AH, Weisenberger DJ, Laird PW et al. Cigarette smoking and colorectal cancer risk by molecularly defined subtypes. Journal of the National Cancer Institute. 2010 Jul;102(14):1012-1022. https://doi.org/10.1093/jnci/djq201
Limsui, David ; Vierkant, Robert A. ; Tillmans, Lori S. ; Wang, Alice H. ; Weisenberger, Daniel J. ; Laird, Peter W. ; Lynch, Charles F. ; Anderson, Kristin E. ; French, Amy J. ; Haile, Robert W. ; Harnack, Lisa J. ; Potter, John D. ; Slager, Susan L ; Smyrk, Thomas Christopher ; Thibodeau, Stephen N ; Cerhan, James R ; Limburg, Paul John. / Cigarette smoking and colorectal cancer risk by molecularly defined subtypes. In: Journal of the National Cancer Institute. 2010 ; Vol. 102, No. 14. pp. 1012-1022.
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abstract = "Background Cigarette smoking is an established risk factor for colorectal cancer. Because colorectal carcinogenesis is a heterogeneous process, we investigated whether cigarette smoking is differentially associated with molecularly defined subtypes of colorectal cancer.Methods We evaluated associations between smoking and incident colorectal cancer, overall and by microsatellite instability (MSI) phenotype (MSI-high vs MSI-low or microsatellite stable), CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation status (BRAF mutation positive or BRAF mutation negative), among 37399 participants in a population-based cohort study (the Iowa Women's Health Study). Cigarette smoking (and other exposures) was assessed by self-report at baseline in 1986, including smoking status (never and ever [former or current]), age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period. Vital status and state of residence were determined by mailed follow-up questionnaires in 1987, 1989, 1992, and 1997 and by linkage to Iowa death certificate records. Nonrespondents were checked via the National Death Index to identify descendants. Participants with newly diagnosed (ie, incident) colorectal cancer were identified through annual linkage with the Iowa Cancer Registry. Archived paraffin-embedded tumor tissue specimens were obtained for 555 patients with colorectal cancer who were diagnosed from January 1, 1986, through December 31, 2002, and MSI status, CIMP status, and BRAF status were determined. Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95{\%} confidence intervals (CIs). Results Ever-smokers were at moderately increased risk for incident colorectal cancer (RR = 1.19, 95{\%} CI = 1.05 to 1.35) compared with never-smokers. Higher risk estimates were observed for current smokers with MSI-high tumors (RR = 1.99, 95{\%} CI = 1.26 to 3.14), CIMP-positive tumors (RR = 1.88, 95{\%} CI = 1.22 to 2.90), and BRAF mutation-positive tumors (RR = 1.92, 95{\%} CI = 1.22 to 3.02). Other smoking-related variables (ie, age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period) were also associated with MSI-high, CIMP-positive, and BRAF mutation-positive tumor subtypes. Conversely, cigarette smoking status (ever vs never) was not associated with the MSI-low or microsatellite stable (RR = 1.00, 95{\%} CI = 0.79 to 1.25), CIMP-negative (RR = 1.02, 95{\%} CI = 0.81 to 1.30), or BRAF mutation-negative subtypes (RR = 1.00, 95{\%} CI = 0.65 to 1.27). Conclusions In this prospective study of older women, cigarette smoking was associated with the MSI-high, CIMP-positive, and BRAF mutation-positive colorectal cancer subtypes, which indicates that epigenetic modification may be functionally involved in smoking-related colorectal carcinogenesis.",
author = "David Limsui and Vierkant, {Robert A.} and Tillmans, {Lori S.} and Wang, {Alice H.} and Weisenberger, {Daniel J.} and Laird, {Peter W.} and Lynch, {Charles F.} and Anderson, {Kristin E.} and French, {Amy J.} and Haile, {Robert W.} and Harnack, {Lisa J.} and Potter, {John D.} and Slager, {Susan L} and Smyrk, {Thomas Christopher} and Thibodeau, {Stephen N} and Cerhan, {James R} and Limburg, {Paul John}",
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TY - JOUR

T1 - Cigarette smoking and colorectal cancer risk by molecularly defined subtypes

AU - Limsui, David

AU - Vierkant, Robert A.

AU - Tillmans, Lori S.

AU - Wang, Alice H.

AU - Weisenberger, Daniel J.

AU - Laird, Peter W.

AU - Lynch, Charles F.

AU - Anderson, Kristin E.

AU - French, Amy J.

AU - Haile, Robert W.

AU - Harnack, Lisa J.

AU - Potter, John D.

AU - Slager, Susan L

AU - Smyrk, Thomas Christopher

AU - Thibodeau, Stephen N

AU - Cerhan, James R

AU - Limburg, Paul John

PY - 2010/7

Y1 - 2010/7

N2 - Background Cigarette smoking is an established risk factor for colorectal cancer. Because colorectal carcinogenesis is a heterogeneous process, we investigated whether cigarette smoking is differentially associated with molecularly defined subtypes of colorectal cancer.Methods We evaluated associations between smoking and incident colorectal cancer, overall and by microsatellite instability (MSI) phenotype (MSI-high vs MSI-low or microsatellite stable), CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation status (BRAF mutation positive or BRAF mutation negative), among 37399 participants in a population-based cohort study (the Iowa Women's Health Study). Cigarette smoking (and other exposures) was assessed by self-report at baseline in 1986, including smoking status (never and ever [former or current]), age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period. Vital status and state of residence were determined by mailed follow-up questionnaires in 1987, 1989, 1992, and 1997 and by linkage to Iowa death certificate records. Nonrespondents were checked via the National Death Index to identify descendants. Participants with newly diagnosed (ie, incident) colorectal cancer were identified through annual linkage with the Iowa Cancer Registry. Archived paraffin-embedded tumor tissue specimens were obtained for 555 patients with colorectal cancer who were diagnosed from January 1, 1986, through December 31, 2002, and MSI status, CIMP status, and BRAF status were determined. Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results Ever-smokers were at moderately increased risk for incident colorectal cancer (RR = 1.19, 95% CI = 1.05 to 1.35) compared with never-smokers. Higher risk estimates were observed for current smokers with MSI-high tumors (RR = 1.99, 95% CI = 1.26 to 3.14), CIMP-positive tumors (RR = 1.88, 95% CI = 1.22 to 2.90), and BRAF mutation-positive tumors (RR = 1.92, 95% CI = 1.22 to 3.02). Other smoking-related variables (ie, age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period) were also associated with MSI-high, CIMP-positive, and BRAF mutation-positive tumor subtypes. Conversely, cigarette smoking status (ever vs never) was not associated with the MSI-low or microsatellite stable (RR = 1.00, 95% CI = 0.79 to 1.25), CIMP-negative (RR = 1.02, 95% CI = 0.81 to 1.30), or BRAF mutation-negative subtypes (RR = 1.00, 95% CI = 0.65 to 1.27). Conclusions In this prospective study of older women, cigarette smoking was associated with the MSI-high, CIMP-positive, and BRAF mutation-positive colorectal cancer subtypes, which indicates that epigenetic modification may be functionally involved in smoking-related colorectal carcinogenesis.

AB - Background Cigarette smoking is an established risk factor for colorectal cancer. Because colorectal carcinogenesis is a heterogeneous process, we investigated whether cigarette smoking is differentially associated with molecularly defined subtypes of colorectal cancer.Methods We evaluated associations between smoking and incident colorectal cancer, overall and by microsatellite instability (MSI) phenotype (MSI-high vs MSI-low or microsatellite stable), CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation status (BRAF mutation positive or BRAF mutation negative), among 37399 participants in a population-based cohort study (the Iowa Women's Health Study). Cigarette smoking (and other exposures) was assessed by self-report at baseline in 1986, including smoking status (never and ever [former or current]), age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period. Vital status and state of residence were determined by mailed follow-up questionnaires in 1987, 1989, 1992, and 1997 and by linkage to Iowa death certificate records. Nonrespondents were checked via the National Death Index to identify descendants. Participants with newly diagnosed (ie, incident) colorectal cancer were identified through annual linkage with the Iowa Cancer Registry. Archived paraffin-embedded tumor tissue specimens were obtained for 555 patients with colorectal cancer who were diagnosed from January 1, 1986, through December 31, 2002, and MSI status, CIMP status, and BRAF status were determined. Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results Ever-smokers were at moderately increased risk for incident colorectal cancer (RR = 1.19, 95% CI = 1.05 to 1.35) compared with never-smokers. Higher risk estimates were observed for current smokers with MSI-high tumors (RR = 1.99, 95% CI = 1.26 to 3.14), CIMP-positive tumors (RR = 1.88, 95% CI = 1.22 to 2.90), and BRAF mutation-positive tumors (RR = 1.92, 95% CI = 1.22 to 3.02). Other smoking-related variables (ie, age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period) were also associated with MSI-high, CIMP-positive, and BRAF mutation-positive tumor subtypes. Conversely, cigarette smoking status (ever vs never) was not associated with the MSI-low or microsatellite stable (RR = 1.00, 95% CI = 0.79 to 1.25), CIMP-negative (RR = 1.02, 95% CI = 0.81 to 1.30), or BRAF mutation-negative subtypes (RR = 1.00, 95% CI = 0.65 to 1.27). Conclusions In this prospective study of older women, cigarette smoking was associated with the MSI-high, CIMP-positive, and BRAF mutation-positive colorectal cancer subtypes, which indicates that epigenetic modification may be functionally involved in smoking-related colorectal carcinogenesis.

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